MRx
JUNE 2019
CLINICAL ALERT
YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS
HOT TOPIC:
GENE THERAPY APPROVED
EDITORIAL
FOR SPINAL MUSCULAR
STAFF ATROPHY
The United States (US) Food and
Drug Administration (FDA) approved
EDITOR IN CHIEF onasemnogene abeparvovec-xioi
Maryam Tabatabai (Zolgensma®) for the treatment of
PharmD patients < 2 years of age with spinal
muscular atrophy (SMA) who have
bi-allelic mutations in the survival
EXECUTIVE EDITOR
motor neuron 1 (SMN1) gene, which
Carole Kerzic
instructs production of a protein critical
RPh
for motor neuron function. SMA is
the leading genetic cause of infant
DEPUTY EDITORS mortality. The most common form, SMA
Jill Bot type 1, occurs in about 1 in 10,000
PharmD newborns, leading to about 500 new
cases per year in the US. Patients with
Stephanie Christofferson SMA type 1 experience progressive
PharmD motor function decline beginning
shortly after birth. If left untreated,
Jessica Czechowski permanent ventilation or death often
PharmD occurs by 2 years of age. Zolgensma
is the only gene replacement therapy
Lara Frick approved for SMA. It is administered
PharmD, BCPS, BCPP as a 1-time intravenous (IV) infusion
over 1 hour and is used as part of a
Leslie Pittman multidisciplinary approach to treat SMA
PharmD type 1. In December 2016, the SMN2-
directed antisense oligonucleotide
nusinersen (Spinraza®) became the
first disease-modifying therapy to
treat SMA (all types) in pediatrics and
adults; maintenance therapy is given
intrathecally every 4 months.
Zolgensma was granted Breakthrough
Therapy and Orphan Drug designations
as well as Priority Review. FDA-approval
of Zolgensma is supported by the
Download at: ongoing STR1VE trial (n=21) and the
magellanrx.com
| JUNE 2019
completed 2-year START trial (n=12,
therapeutic cohort). Both studies
enrolled patients with SMA type 1.
Treatment with Zolgensma led to
significant improvement in reaching
developmental motor milestones,
such as head control, sitting without
support, and/or standing/walking
without assistance compared to the
natural history of the disease. A durable
effect of nearly 4 years was reported
in the START long-term follow-up.
Zolgensma carries a Boxed warning
for acute serious liver injury.
Avexis/Novartis set a wholesale
acquisition cost (WAC) of $2.125 million
for the 1-time Zolgensma dose, making
it the world’s most expensive drug.
The Institute for Clinical and Economic
Review (ICER) published a value-based
price benchmark for Zolgensma of $1.2
million to $2.1 million to reach a cost-
effectiveness threshold of $100,000 to
$150,000 per life year gained (LYG). This
amount assumes durable effectiveness
and considers the positive results of
the SPR1NT trial in presymptomatic
patients (< 6 months of age). Safety
and efficacy of repeat administration
have not been studied, nor has use in
patients with advanced SMA (complete
limb paralysis or permanent ventilator
dependence). While Spinraza use after
Zolgensma therapy has been reported,
clinical benefits and risks have not been
established. Zolgensma is available as
patient-specific kits through a specialty
pharmacy distributor. The company is
working closely with payers to create
5-year outcome-based agreements and
novel pay-over-time options.

BIOSIMILAR CORNER
FDA GUIDANCE ON INTERCHANGEABLE
BIOLOGICS
To date, 19 biosimilar products have been approved in
the US, 7 of which are commercially available. Currently,
no biosimilar is considered to be interchangeable with
its reference product; therefore, pharmacists cannot
substitute a biosimilar for the reference product
without involvement of the prescriber. As part of their
Biosimilars Action Plan, the FDA recently provided
standards for approval of interchangeable biologic
agents in their final guidance titled, “Considerations
in Demonstrating Interchangeability with a Reference
Product Guidance for Industry.”
The FDA advises that in addition to showing
biosimilarity, the sponsor must demonstrate that
the proposed interchangeable biologic product is
expected to yield the same clinical result compared to
the reference product for all of the reference product’s
FDA-approved indications. Data necessary to meet the
interchangeability standards may include critical quality
attributes (e.g., safety, purity, potency), target/receptor
interactions, pharmacokinetics, and immunogenicity.
Any difference between the proposed interchangeable
product and the reference product should be justified
and proven that it will not prohibit the same clinical
results as the reference product in any given patient.
In addition, if the product is administered more
than once to a patient, alternating use between
the proposed interchangeable biologic and the
reference product should not lead to increased safety
risks or reduced efficacy. Considerations regarding
interchangeability of container closure systems and
delivery device components are also addressed.
Furthermore, insulins, historically regulated by the
FDA as small molecules, will be deemed biological
products as of March 23, 2020. This transition will
allow approval of insulins that are interchangeable
with their brand competitors.
CVD PRIMARY PREVENTION GUIDELINES
The American College of Cardiology (ACC) and American
Heart Association (AHA) released a new guideline on
the primary prevention of cardiovascular disease (CVD).
The guideline emphasizes the importance of a healthy
lifestyle in patients with diabetes, hypercholesterolemia,
or hypertension. The ACC/AHA recommends a
multidisciplinary, team-based approach and shared
decision-making between the patient and physician.
2 | JUNE 2019
According to the guideline, cardiovascular (CV) risk factors
should be assessed every 4 to 6 years in patients aged
20 to 39 years to determine the need for treatment.
The race- and sex-specific Pooled Cohort Equation (PCE)
is recommended to estimate 10-year atherosclerotic
CVD (ASCVD) risk for asymptomatic adults aged 40 to
79 years. While use of PCE is best supported in non-
Hispanic populations, other risk assessment tools, such
as the Framingham CVD risk score, Reynolds risk score,
Systematic COronary Risk Evaluation (SCORE), and QRISK/
JBS3, can be considered in Hispanics or populations with
enhanced risk (e.g., HIV infection, chronic inflammatory
disease, low socioeconomic status). Use of the coronary
artery calcium (CAC) score is reasonable to estimate
ASCVD risk when uncertainty still exists. In addition,
serum lipids should be assessed starting in childhood.
Statins remain first-line therapy for hypercholesterolemia.
Due to their proven CV benefits in patients with type 2
diabetes mellitus (T2DM), sodium-glucose cotransporter
2 (SGLT 2) inhibitors and glucagon-like peptide-1 receptor
agonists (GLP-1RA) are recommended in patients with
T2DM and additional CVD risk factors. While low-dose
aspirin is established for secondary prevention of ASCVD,
because of a lack of net benefit, it should only be considered
for primary prevention in select patients aged 40 to 70
years who are not at increased bleeding risk.
BEHAVIORAL HEALTH CORNER
INSOMNIA TREATMENT SAFETY ALERT
The FDA released a Drug Safety Communication
regarding rare but serious injuries associated with
prescription sedative-hypnotic agents used to treat
insomnia. Over a 26-year period, a total of 66 cases
of complex sleep behaviors have been reported in
patients taking eszopiclone (Lunesta®), zaleplon
(Sonata®), and zolpidem (Ambien®, Ambien CR®,
Edluar®, Intermezzo®, Zolpimist®). These included
sleepwalking, sleep driving, and other activities while
not fully awake. Some cases resulted in death, even
in patients taking the lowest recommended dose. As
a result, the FDA is strengthening the warnings for the
products listed to include a Boxed warning regarding
sleep behaviors. Furthermore, a contraindication
will be added advising prescribers to avoid use in
patients who have previously experienced complex
sleep behavior while taking any of these agents.
Patients should stop taking their prescribed insomnia
agent and contact their physician if they experience
complex sleep behavior.
DRUG INFORMATION HIGHLIGHTS
• U pdate on consumer level recalls of generic
antihypertension medications due to potential human
carcinogenic impurities: Vivimed Life Sciences issued
a recall of 19 lots of losartan potassium 25 mg, 50 mg,
and 100 mg tablets due to the detection of N-nitroso-
N-methyl-4-amino butyric acid (NMBA) above the FDA’s
acceptable exposure limit. Moreover, the FDA published
2 new tests, HRMS and RapidFire-MS/MS, as options for
regulators and industry to detect nitrosamine impurities.
• As part of the continued effort to tackle the opioid crisis,
the FDA unveiled a new “Remove the Risk” campaign
that provides a stepwise approach for patients to
properly dispose of unused prescription opioids.
Medicine take-back programs are the preferred method
to discard unneeded medicines, including opioids.
Authorized locations include law enforcement facilities
and pharmacies in retail, hospital, or clinic settings.
Mail-back programs or “drop-boxes” are also available
in some locations.
• Novartis announced a consumer level voluntary recall
of 3 lots of eltrombopag (Promacta®) 12.5 mg for oral
suspension due to a risk of potential peanut flour
contamination. Exposure to contaminated product can
lead to hypersensitivity reactions, including anaphylaxis,
in patients with a sensitivity to peanut antigens. No
adverse events have been reported. Eltrombopag is
indicated to treat chronic immune thrombocytopenia
and is distributed through specialty pharmacies.
PIPELINE NEWS: UPCOMING PRESCRIPTION DRUG/BIOSIMILAR USER FEE ACT (PDUFA/BsUFA) DATES
• June 2019: bevacizumab, biosimilar to Genentech’s
Avastin®; IV vascular endothelial growth factor (VEGF)
inhibitor; non-small cell lung cancer, colorectal cancer,
ovarian cancer, renal cancer; Pfizer.
• June 2019: onabotulinumtoxinA (Botox®); intradermal
neurotoxin; pediatric upper limb spasticity; Allergan.
• June 2019: rituximab, biosimilar to Genentech’s Rituxan®;
IV anti-CD20 antibody; non-Hodgkin’s lymphoma,
rheumatoid arthritis; Pfizer.
• June 2019: trastuzumab, biosimilar to Genentech’s
Herceptin®; IV human epidermal growth factor receptor
2 (HER2)/neu receptor antagonist; breast cancer, gastric
cancer; Allergan/Amgen.
• June 10, 2019: glucagon pen; SC recombinant glucagon;
severe diabetes-related hypoglycemia; Xeris.
• June 17, 2019: pembrolizumab (Keytruda®); IV
programmed death receptor-1 (PD-1) inhibitor; small cell
lung cancer; Merck.
3 | JUNE 2019
• The American Urological Association (AUA) released
consensus guidelines on the evaluation, testing, treatment,
and follow-up of recurrent urinary tract infections (UTI)
in women. Initial treatment should be based on the
local antibiogram. A short course (generally ≤ 7 days)
of antibiotics is considered reasonable to treat acute
cystitis; however, antibiotic-resistant cases may require
parenteral antibiotics (≤ 7 days). To decrease risk of
future UTIs, antibiotic prophylaxis and/or cranberry
consumption may be considered. Additionally, in peri-
and post-menopausal women, risk of recurrent UTIs
may be decreased with vaginal estrogen therapy if no
contraindications exist.
• ICER revised its value-based benchmark ranges for the
proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitor alirocumab (Praluent®). The new ranges are
$2,300 to $3,500 per year in all eligible patients and
$2,700 to $4,000 per year for higher-risk patients with
low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL
despite statin therapy. The changes are based on further
analysis of the ODYSSEY Outcomes trial, which reported
a similar benefit with alirocumab in all patient groups,
including those with LDL-C ≤ 100 mg/dL. The value-
based benchmark indicates a net price range that is
consistent with the treatment’s added benefit to patients
and the healthcare system.
• June 20, 2019: mannitol; inhaled mucolytic; cystic fibrosis
(CF); Chiesi.
• June 21, 2019: bremelanotide; SC melanocortin agonist;
female sexual arousal disorder; AMAG.
• June 21, 2019: olopatadine/mometasone furoate; nasal
antihistamine/corticosteroid; seasonal allergic rhinitis;
Glenmark.
• June 25, 2019: celiprolol; oral beta-adrenergic antagonist;
Ehlers-Danlos syndrome; Acer.
• June 26, 2019: dupilumab (Dupixent®); SC interleukin (IL)-4
inhibitor; nasal polyposis; Regeneron.
• June 28, 2019: avatrombopag (Doptelet®); oral
thrombopoietin receptor agonist; immune
thrombocytopenic purpura; Dova.
• June 28, 2019: eculizumab (Soliris®); IV complement
inhibitor; neuromyelitis optica; Alexion.
RECENT FDA APPROVALS
DRUG NAME
DESCRIPTION
MANUFACTURER
New Drugs
etanercept-ykro • BLA approval 04/25/2019; biosimilar to Amgen’s etanercept (Enbrel®)
(Eticovo™) • Indicated for the treatment of adults with rheumatoid arthritis (RA), psoriatic arthritis (PsA),
Samsung Bioepis or ankylosing spondylitis (AS), pediatric patients ages ≥ 2 years with polyarticular juvenile
idiopathic arthritis (JIA), and pediatric patients ages ≥ 4 years with plaque psoriasis (PSO)
• Tumor necrosis factor (TNF) inhibitor
• Injection: 25 mg/0.5 mL, 50 mg/mL single-dose prefilled syringes
• Recommended weight-based dosing in patients ≥ 63 kg is 50 mg SC once weekly, with the
exception of adult PSO which is 50 mg SC twice weekly for 3 months, then once weekly
thereafter
»» No dosage form exists for Eticovo that allows weight-based dosing for pediatric
patients < 63 kg; use an alternative reconstituted lyophilized powder etanercept
product for patients < 63 kg
• Boxed warnings for serious infections and malignancies
• Product availability may be delayed due to litigation
halobetasol • NDA approval 04/25/2019
propionate/ • Indicated for the topical treatment of PSO in adults
tazarotene • Combination topical steroid and retinoid
(Duobrii™) • Topical lotion: halobetasol 0.01%/tazarotene 0.045% in 45 g, 60 g, and 100 g tubes
Bausch Health • Recommended dosage is a thin layer applied topically once daily to affected areas
• Product availability is anticipated in June 2019
dengue tetravalent • BLA approval 05/01/2019; Priority Review
vaccine, live • Indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2,
(Dengvaxia®) 3, and 4 in adolescents aged 9 to 16 years with laboratory-confirmed previous dengue
Sanofi Pasteur infection and living in endemic areas
• Viral vaccine antigen
• Injection: lyophilized powder for suspension with supplied diluent
• Recommended regimen is three 0.5 mL doses administered SC 6 months apart (months 0,
6, and 12)
dapagliflozin/ • NDA approval 05/02/2019
saxagliptin/ • Indicated for improved glycemic control in adults with T2DM as an adjunct to diet and
metformin exercise
extended-release »» Not indicated for type 1 diabetes mellitus
(ER) »» Intended for patients currently taking metformin
(Qternmet® XR) • Combination SGLT2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, and biguanide
AstraZeneca • Tablets (dapagliflozin/saxagliptin/metformin ER): 2.5 mg/2.5 mg/1,000 mg,
5 mg/2.5 mg/1,000 mg, 5 mg/5 mg/1,000 mg, and 10 mg/5 mg/1,000 mg
• Recommended dosage is 1 tablet once daily in the morning with food
• Boxed warning for lactic acidosis
ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics
License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not
conducted by or for the applicant.

4 | JUNE 2019
RECENT FDA APPROVALS continued
DRUG NAME
DESCRIPTION
MANUFACTURER
New Drugs continued
tafamidis • NDA approvals 05/03/2019; Breakthrough Therapy (Vyndaqel); Orphan Drug (both);
meglumine Priority Review (Vyndaqel)
(Vyndaqel®)/ • Indicated for the treatment of adults with cardiomyopathy of wild type or hereditary
tafamidis transthyretin-mediated amyloidosis to reduce CV mortality and CV-related hospitalization
(Vyndamax™) • Transthyretin stabilizers
Pfizer • Capsules: tafamidis meglumine 20 mg, tafamidis 61 mg
• Recommended dosage is tafamidis meglumine 80 mg (as four 20 mg capsules) or tafamidis
61 mg oral once daily
• Vyndamax and Vyndaqel are not substitutable on a milligram-per-milligram basis
amifampridine • NDA approval 05/06/2019; Orphan Drug; Priority Review
(Ruzurgi®) • Indicated for Lambert-Eaton myasthenic syndrome (LEMS) in patients aged 6 to < 17 years
Jacobus • Potassium channel blocker
• Tablets: 10 mg, scored and can be used to prepare a 1 mg/mL suspension
• Recommended dosage is weight-based
»» Patients weighing ≥ 45 kg: initial dose is 15 mg to 30 mg daily in divided doses; may
increase to a maximum of 100 mg per day; maximum single dose is 30 mg
»» Patients weighing < 45 kg: initial dose is 7.5 mg to 15 mg daily in divided doses; may
increase to a maximum of 50 mg per day; maximum single dose is 15 mg
midazolam • NDA approval 05/17/2019; Orphan Drug
(Nayzilam®) • Indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure
Proximagen activity that are distinct from a patient’s usual seizure pattern in patients with epilepsy
aged ≥ 12 years
• Benzodiazepine
• Nasal spray: 5 mg/0.1 mL
• Recommended dosage is 1 spray (5 mg) into 1 nostril for the initial dose; 1 additional spray
(5 mg) into the opposite nostril may be administered after 10 minutes if the patient has
not responded to the initial dose; do not use > 2 doses to treat a seizure cluster
• Boxed warning for risks from concomitant use with opioids
• Scheduled IV controlled substance
Expanded Indications
alirocumab • sBLA approval 04/26/2019
(Praluent®) • New indication to reduce the risk of myocardial infarction, stroke, and unstable angina
Sanofi requiring hospitalization in adults with established CVD
• Expanded indication as an adjunct to diet, alone or in combination with other lipid-lowering
therapies, for the treatment of adults with primary hyperlipidemia to reduce LDL-C
• Recommended dosage is 75 mg SC once every 2 weeks or 300 mg SC once every 4 weeks;
dose may be adjusted to a maximum of 150 mg SC every 2 weeks
belimumab • sBLA approval 04/26/2019
(Benlysta®) • Expanded indication for the treatment of active, autoantibody-positive, systemic lupus
Human Genome erythematosus in patients who are receiving standard therapy to include those aged 5 to
Sciences 17 years
• Recommended dosage is 10 mg/kg administered IV over 1 hour at 2-week intervals for the
first 3 doses and at 4-week intervals thereafter; SC administration is only approved for use
in adults
ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics
License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not
conducted by or for the applicant.

5 | JUNE 2019
RECENT FDA APPROVALS continued
DRUG NAME
DESCRIPTION
MANUFACTURER
Expanded Indications continued
ivacaftor • sNDA approval 04/29/2019
(Kalydeco®) • Expanded indication for the treatment of CF in patients with 1 mutation in the CF
Vertex transmembrane conductance regulator (CFTR) gene to include patients aged 6 months to
< 12 months
• Recommended weight-based dosage in this age group:
»» Patients weighing 5 kg to < 7 kg: one 25 mg granule packet every 12 hours
»» Patients weighing 7 kg to < 14 kg: one 50 mg granule packet every 12 hours
»» Patients weighing ≥ 14 kg: one 75 mg granule packet every 12 hours
• Mix contents of packet with 5 mL of soft food or liquid and administer orally with fat-
containing food
glecaprevir/ • sNDA approval 04/30/2019
pibrentasvir • Expanded indications to include patients as young as 12 years or weighing ≥ 45 kg for
(Mavyret™) the treatment of chronic hepatitis C virus (HCV) genotype (GT) 1, 2, 3, 4, 5, or 6 infection
Abbvie in patients without cirrhosis or with compensated cirrhosis and the treatment of HCV GT1
infection in patients previously treated with a regimen containing an HCV NS5A inhibitor or
an NS3/4A protease inhibitor, but not both
• Recommended dosing is 3 tablets orally once daily with food
ivosidenib • sNDA approval 05/02/2019; Orphan Drug; Priority Review
(Tibsovo®) • Expanded indication for the treatment of adults with newly diagnosed acute myeloid
Agios leukemia (AML) who are ≥ 75 years of age or who have comorbidities that preclude use of
intensive induction chemotherapy
• Recommended dosage is 500 mg orally once daily with or without food until disease
progression or unacceptable toxicity, avoiding high-fat meals
ado-trastuzumab • sBLA approval 05/03/2019; Breakthrough Therapy; Priority Review
emtansine • Expanded indication for adjuvant treatment of patients with HER2-positive early breast
(Kadcyla®) cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-
Genentech based treatment
• Recommended dosage is 3.6 mg/kg given IV every 3 weeks for a total of 14 cycles unless
there is disease recurrence or unacceptable toxicity
calcipotriene • sNDA approval 05/06/2019
(Sorilux™) • Expanded indication to treat PSO of the scalp and body in patients as young as 12 years
Mayne • Recommended dosage is a thin layer applied topically to affected areas twice daily
incobotulinumtoxinA • sBLA approval 05/10/2019
(Xeomin®) • E xpanded indication for the treatment of blepharospasm in adult patients; no longer
Merz limited to use in patients previously treated with onabotulinumtoxinA (Botox)
• Recommended initial total dose is 50 Units (25 Units per eye) administered
intramuscularly
ramucirumab • sBLA approval 05/10/2019
(Cyramza®) • Expanded indication as a single agent for the treatment of hepatocellular carcinoma
Eli Lilly in patients with an alpha fetoprotein (AFP) ≥ 400 ng/mL and have been previously
treated with sorafenib
• Recommended dosage is 8 mg/kg administered IV every 2 weeks
ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics
License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not
conducted by or for the applicant.

References:
acc.org auanet.org avexis.com evaluate.com fda.gov icer-review.org

6 | JUNE 2019 © 2019, Magellan Health. All rights reserved.